Rare single-gene variants exhibit a high risk of mental health conditions, Geisinger study shows

NEW YORK — Researchers at Geisinger Health System have produced data that provide a fuller picture of the prevalence of genetic variants associated with mental health disorders, and believe their findings provide support for more routine incorporation of genetic testing into patient care.

Researchers analyzed genomic test results and electronic health record data from patients enrolled in Geisinger’s MyCode community health initiative, a precision medicine project, and found that a subset with genetic variants associated with neurodevelopmental psychiatric disorders (NPD) such as intellectual disability, schizophrenia, and bipolar disorder, According to the results published in American Journal of Psychiatry Last month.

The study authors concluded that testing for such genetic variants among patients with these types of mental health disorders could improve clinical outcomes. “Diagnostic testing to identify rare disease-causing variants should be offered to individuals with symptoms of NPD, given the significant personal benefit of genetic diagnosis and the potential for improving outcomes through proactive medical monitoring,” they wrote.

For the study, the researchers analyzed the sequences of the exomes of more than 90,000 patients for disease-causing single-gene variants in 94 genes known to increase the risk of NPDs. The study included patients in the DiscovEHR cohort, a subset of MyCode whose genetic test results correlated with anonymized EHR data. Geisinger is collaborating on the DiscovEHR effort with the Regeneron Genetics Center, a research and development subsidiary of the drug company Regeneron.

In all, 0.34 percent of the 90,595 patients had at least one genetic variant associated with NPD. When taking results from previous search In Geisinger’s study which identified patients with 31 polygenic copy number variants (CNV) associated with NPDs, collectively about 1.1 percent of the patients — one of approximately 89 — carried either a related variant of one gene or a CNV, according to the study authors.

“This study confirms the important contributing role of rare genetic variants in NPDs,” the study authors wrote.

Moreover, analysis of the ICD-9 and -10 diagnostic codes revealed that one-third of patients carrying a genetic variant were diagnosed with NPD. When the researchers focused on patients with variants in eight genes associated with NPD — TRIO, NAA15, ASH1L, ZNF292, IRF2BPL, CLTC, GIGYF1 and POGZ — they found that between 40 percent and 53 percent of the group had been diagnosed with mental illness. Health disorder, such as intellectual disability, schizophrenia, and bipolar disorder.

“This is very substantial,” said Krista Martin, a civil society official in Danville, Pennsylvania. Geisinger and founding director of the Health System’s Institute for Developmental Medicine and Autism, and senior author on the paper. Martin suspects that the proportion of pathogen carriers with a mental health disorder is likely much higher than a third, but researchers may not be able to identify these patients due to electronic health record data limitations.

For example, the current analysis would have missed patients whose diagnoses of NPD were documented in unstructured clinical notes. Patients may also seek mental health care outside of Geisinger, or they may have mild presentations of NPD that their doctors have not diagnosed.

The study reports that 14.6 percent of patients without a relevant genetic variant were also diagnosed with NPD. NPDs are “extremely complex,” the study authors wrote, with a range of clinical presentations and contributing factors. The effects of genetic variants are modified by genomic, environmental, and experiential factors across an individual’s life.

The paper represents one of the first studies to look at the prevalence of single gene variants associated with NPD across a large adult population, according to Martin. Much of the research to date has used groups of patients who undergo genetic testing after experiencing symptoms of NPD.

The study by Martin and his colleagues demonstrates the extent to which people not diagnosed with NPD have such genetic variants — an ongoing question in developmental neurogenetics, said Aaron Besterman, assistant professor in the department of psychiatry at the University of California, San Diego. and a psychiatrist in the Child and Adolescent Psychiatry Service at Rady Children’s Hospital – San Diego.

“If we didn’t look at the general population, we wouldn’t know for sure” the actual prevalence of variants associated with NPD, said Bestermann, who was not involved in Geisinger’s study. In his view, this study confirms that while most people do not have genetic variants associated with NPD, there are many more that may have been previously appreciated.

For patients with NPDs, genetic results can inform their medical management by determining whether they are at increased risk for other diseases or providing more information about their prognosis. And if parents receive genetic results for a child, the results may have implications for future pregnancies.

For example, deletion of chromosome 17 is associated with autism spectrum disorder and schizophrenia, as well as an increased risk of developing diabetes in young adulthood. “Knowing this information allows you to try and manage diabetes risk going forward,” Martin said.

Although identifying disease-causing variants may not “radically” change the management of an NPD patient, Besterman hopes that advances in pharmacogenetics and even gene therapy could eventually change that. He is interested to see if future research indicates changes in the management of care for patients who have a genetic variant but do not have symptoms of NPD.

A geneticist by training, Martin said one of her goals as a Geisinger CSO is to “bring genetics out of the genetics clinic and into broader health care.”

Diagnostic genetic tests for NPDs are available today, but they aren’t used much outside of clinical genetic settings, researchers from Geisinger and the Hospital for Sick Children in Toronto write in an article in Current opinion in genetics and development Last year, he called on the industry to create multidisciplinary consensus recommendations about genetic testing for children and adults with NPD.

Recommendations for genetic testing can vary by society. The American College of Medical Genetics and Genomics recommends that those who have it be offered genetic testing Autismas well as exome or genome sequencing of affected pediatric patients Developmental delay or intellectual disability. The American Psychiatric Association lists genetic testing as a suggested evaluation for Schizophrenia Patients in practice guidelines. the International Society of Psychogenic GeneticsFragile X molecular testing and chromosomal microarray analysis, by contrast, is part of the standard workup for those with autism, intellectual disability, and developmental delay, and exome sequencing is increasingly being used as a first-line test; The society does not have any molecular testing recommendations for schizophrenia.

However, even in areas such as autism, where there is broad agreement on the usefulness of genetic testing, uptake has been low. Study 2021 in Frontiers in Pediatrics It has been noted that between 16.5 percent and 45 percent of pediatric patients with autism and 43 percent of patients with intellectual disability have had genetic testing, despite the recommendations of many medical societies.

The researchers wrote in the journal Current opinion in genetics and development Article. In cases where NPD professionals wish to perform genetic evaluations of their patients, they tend to refer patients to medical geneticists to determine which tests to order. This can create a bottleneck, as medical geneticists are in short supply, and patients may not keep referral appointments.

At Geisinger, the health system implemented a model in which clinicians at ADMI order exome sequencing of pediatric patients with autism, intellectual disability, and developmental delays, Martin said. In fact, it is one of the first steps doctors take after providing a diagnosis. Genetic counselors then work with members of the clinical team to review genetic results and pass this information on to patients.

“We can’t send everyone to a geneticist just to have them order testing,” she said. “It creates a huge bottleneck with waiting lists.”

Genetic testing for bipolar disorder and schizophrenia is “on our radar” at Geisinger, Martin added, but the health system continues to research the diagnostic payoff and how to use those findings in clinical care.

“We need to collect more evidence [on medical utility]Martin said previous search NPD patients have previously reported that genetic findings are helpful, suggesting at least a personal benefit — with many patients appreciating that there is a medical explanation for their symptoms. It “provides an answer to the individual as to why he has this condition,” she said.